Heme oxygenase oxidizes heme to biliverdin, CO, and iron. This is the only physiological mechanism for heme, degradation, although pathological heme degradation processes exist that do not yield biliverdin. All three heme oxygenase products are now thought to have important physiological roles: biliverdin as an antioxidant, CO as a signaling molecule akin to NO, and iron as a source of the metal for new heme synthesis and, under pathological conditions, as a catalyst of oxidative damage. Heme oxygenase thus fills a pivotal role in physiological and pathological processes. The long-term goal of this project is to elucidate the mechanisms of normal and abnormal heme degradation and their consequences. The immediate goal is to determine the structure, mechanism, and function of heme oxygenase. The investigator proposes to: (a) complete determination of the crystal structure of human heme oxygenase-1 and its substrate, product, and ligand complexes; (b) elucidate the catalytic mechanism of heme oxygenase-1 with emphasis on identifying all the reaction intermediates, establishing the kinetic mechanism, and identifying the catalytic residues; (c) clarify the mechanisms of the individual steps in the transformation catalyzed by heme oxygenases and the mechanistic relationship of the heme oxygenases to other catalytic hemoproteins, notably to the peroxidases and cytochrome P450 enzymes; (d) explore the mechanism of the abnormal H2O2 -dependent degradation of heme groups to monopyrrole and dipyrrole products; and (e) develop non-porphyrin, inhibitors of the heme oxygenases that do not inhibit the nitric oxide synthases or guanylyl cyclase. The results should help to clarify the molecular aspects of normal and abnormal heme catabolism, shed light on the physiological roles of the heme oxygenase products, and advance our fundamental understanding of hemoprotein structure and function.